6-Allyl-N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-ergoline-8βcarboxamide—international non-proprietary name cabergoline—of formula (I)
is a potent dopamine agonist and is useful as anti-Parkinson drug and as prolactin inhibitor (Eur. J. Med. Chem. 1989, 24, 421-426 and U.S. Pat. No. 5,382,669).
Cabergoline (I) was firstly prepared according to U.S. Pat. No. 4,526,892 by reaction of 6-allyl-ergoline-8β-carboxylic acid (II) with 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide (EDC) (Scheme 1).

In this case both regioisomers (I) and (III) were obtained and the yield of the isolated cabergoline (I) is only approx. 21% as a consequence of isolation difficulties, considering that the yield of compound (II) prepared from (XIII) according to the state of the art is 70%.
Eur. J. Med. Chem. 1989, 24, 421-426 describes another method for the preparation of Cabergoline (I), which is based on the direct reaction of 6-allyl-N-[3-(dimethylamino)propyl]-ergoline-8β-carboxamide (IV) with ethyl isocyanate (EtNCO) (Scheme 2).

Since this reaction leads to equilibrium, it requires the use of a large excess of ethyl isocyanate (up to 40 equivalents) for reasonable conversion and must be conducted at above 100° C. in toluene for several hours. The use of large quantities of toxic ethyl isocyanate under drastic reaction conditions presents a serious hazard for the large-scale preparation of cabergoline (I). In addition, conversion to (I) is incomplete and competitive acylation of the indole nitrogen forming compounds (V) and (VI) occurs. This side reaction complicates the product purification and reduces the yield, which is only approx. 58%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
The method proposed in U.S. Pat. No. 5,382,669 and Syn. Lett. 1995, 605-606 showed that catalysis by copper salts in the presence of phosphine ligands permitted the ethyl isocyanate reaction to be run at room temperature with only 3 equivalents of ethyl isocyanate. However, despite of moderation in reaction conditions the conversion and the ratio of cabergoline (I) and the byproducts (V and VI) are not much different from the uncatalyzed thermal reaction. The yield is only approx. 48% and 57%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
J. Org Chem. 2002, 67, 7147-7150 describes an ethyl isocyanate-free method for the production of cabergoline (I) that solves the problem of completing acylation of indole nitrogen, too.
The first step is the protection of indole nitrogen of amide (IV) preferably as tert-butyl carbamate (VII).
Extension of the amide side chain is done by deprotonation of compound (VII) with sodium hexamethyldisilazide (NaHMDS) followed by trapping the anion with phenyl chloroformate (PhOCOCl) to yield the phenyl carbamate (VIII).
Reaction of compound (VIII) with ethylamine hydrochloride (EtNH2xHCl) gives BOC-cabergoline (IX) but also generates the ethylamide (X). The deprotection is done from the mixture of (IX) and (X) with 1N aqueous hydrochloric acid. The purified cabergoline (I) is then isolated by basification followed by chromatography on silica. (Scheme 3).

In this approach the deprotonating step requires special cold reactor and strictly anhydrous circumstances. These requirements can hardly be satisfied in the course of large-scale preparation and the yield is only approx. 52%, considering that the yield of compound (VII) prepared from (XIII) according to the state of the art is 66%.
According to US 2002/0177709 A1 Patent Application cabergoline (I) may be prepared by silylating amide (IV) with a silylating agent (e.g. trimethylsilyl trifluoromethane sulfonate—TMSOTf), reacting the obtained product (XI) with ethyl isocyanate (EtNCO) followed by desilylation of intermediate (XII) (Scheme 4).

The disadvantage of this process is, that the silylating step requires strictly anhydrous circumstances. Otherwise, the reaction with ethyl isocyanate runs too long (24 hours) raising the safety hazard in the course of large-scale preparation and the yield is approx. 65%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
Several crystalline forms of Cabergoline (I) are known.
I L Farmaco 1995, 50 (3), 175-178 describes the preparation of crystalline form I. This solvated anhydrate product is crystallized from diethyl ether.
WO 01/70740 A1 Patent Application describes a new process for the preparation of crystalline form I from the new crystalline form V. The form V—which is toluene solvate—is prepared from the mixture of the purified cabergoline (I) with toluene and diethyl ether by a long-lasting complicated process, at low reaction temperature, and the yield is only 45%. The crystalline form I is prepared by drying the form V in vacuum.
WO 01/72746 A1 Patent Application describes the preparation of crystalline form VII from the crystalline form I. By this process the suspension of form I in n-heptane or 1,4-dioxane is stirred for 48 hours, and then the suspension was filtered to obtain the crystalline form VII. The yield is 45.2%.
WO 01/72747 A1 Patent Application describes the crystalline form II and a process for its preparation with approx. 70% yield by stirring the cabergoline (I) for several days in an organic solvent (eg. diethyl ether) at low temperature.